Multidirectional desymmetrization of pluripotent building block en route to diastereoselective synthesis of complex nature-inspired scaffolds

Abstract

Octahydroindolo[2,3-a]quinolizine ring system forms the basic framework comprised of more than 2000 distinct family members of natural products. Despite the potential applications of this privileged substructure in drug discovery, efficient, atom-economic and modular strategies for its assembly, is underdeveloped. Here we show a one-step build/couple/pair strategy that uniquely allows access to diverse octahydroindolo[2,3-a]quinolizine scaffolds with more than three contiguous chiral centers and broad distribution of molecular shapes via desymmetrization of the oxidative-dearomatization products of phenols. The cascade demonstrates excellent diastereoselectivity, and the enantioselectivity exceeded 99% when amino acids are used as chiral reagents. Furthermore, two diastereoselective reactions for the synthesis of oxocanes and piperazinones, is reported. Phenotypic screening of the octahydroindolo[2,3-a]quinolizine library identifies small molecule probes that selectively suppress mitochondrial membrane potential, ATP contents and elevate the ROS contents in hepatoma cells (Hepa1-6) without altering the immunological activation or reprogramming of T- and B-cells, a promising approach to cancer therapy.

Fig. 1

Representative examples of bioactive octahydroindolo[2,3-a]quinolizine systems

Fig. 2

Multidirectional utilization of oxidative-dearomatization building blocks. a Previous and current approaches utilizing the building blocks derived from oxidative-dearomatization reaction. b Three-directional build/couple/pair strategy for the access of diverse molecular shapes

Fig. 3

Diastereoselective synthesis of polycyclic octahydroindolo[2,3-a]quinolizines. ORTEP diagrams of compounds 5a, 5c, and 6c. PhI(OAc)₂, (diacetoxyiodo)benzene; MeOH methanol, DMP Dess-Martin periodinane

Fig. 4

Synthesis of skeletally diverse collections of octahydroindolo[2,3-a]quinolizines. a Asymmetric synthesis of polycyclic octahydroindolo[2,3-a]quinolizines. b Regioselective synthesis of octahydroindolo[2,3-a]quinolizines

Fig. 5

Post-pairing transformations of octahydroindolo[2,3-a]quinolizines. a OsO₄-catalyzed synthesis of the compounds 14 and 15. b A proposed mechanism for the OsO₄ catalyzed formation of compound 14

Fig. 6

Post-pairing transformations of octahydroindolo[2,3-a]quinolizines. a OsO₄-catalyzed dihydroxylation. b NBS-mediated synthesis of spiro-oxindole polycyclic systems. AcOH acetic acid, THF tetrahydrofuran

Fig. 7

Tandem synthesis of oxocanes employing aniline and quinone derivatives. a Diatereoselective synthesis of oxocanes. b A proposed mechanism for the formation of oxocanes. MS molecular sieves

Fig. 8

Cascade transformation of quinones to piperazinones utilizing amino acids as substrates. a Asymmetric synthesis of piperazinones. b A proposed mechanism for the formation of piperazinones. MS molecular sieves

Fig. 9

Screening of a pilot library on cellular functions in Hepa1–6. a Effect of compounds 5c and 26c on ATP. b Effect of compounds 5c and 26c on mitochondrial membrane potential. c Effect of compounds 5c and 26c on cellular redox potential. d Effect of compounds 5c and 26c on cellular proliferation. e Cytotoxicity of compounds 5c and 26c. Error bars indicate standard deviation based on three replicated calculations. Significance was tested using an ANOVA test, with Dunnett’s multiple comparison test

Fig. 10

Screening of a pilot library on cellular functions in Hepa1–6. a Effect of compounds 5c and 26c on immune cell proliferation in lymphocytes or isolated T cells. a, b Effect of compounds 5c and 26c on CD3⁺ T lymphocytes. c, d Effect of compounds 5c and 26c on B220⁺ B lymphocytes. e, f Effect of compounds 5c and 26c on isolated T cells. Error bars indicate standard deviation based on three replicated calculations. Significance was tested using an ANOVA test, with Dunnett’s multiple comparison test. *p < 0.05